The previous section of this book
established that there is no safe dose or dose-rate of low-LET ionizing
radiation, with respect to induction of human cancers.

This section takes up a separate issue: The general
practice, by the radiation community, of reducing
estimates of cancer-risk if the exposure is low or slow.
This is the usual practice, whether or not any
suggestion is made of a completely safe dose or
dose-rate.

With the exceptions of breast-cancer and
thyroid-cancer, the radiation community has been
making its cancer risk-estimates for low-LET, low-dose
exposures by asserting that the "effectiveness" or
carcinogenic potency per rad is considerably less at
low total doses than at high total doses, and also that
the risk is considerably less if a dose is received slowly
than if the same dose is received all at once.

In other words, the radiation community reduces
estimates of risk-per-rad, observed in humans at acute
high doses, by factors which are often called "dose
effectiveness factors." There are two possible kinds of
such factors: (1) one for the alleged reduction in
cancer-risk per rad in going from a high total dose to a
low total dose, all delivered acutely, and (2) one for
going from a high dose-rate to a low dose-rate.

Definition and Magnitude of "DREFS" :

The NCRP (National Council on Radiation Protection)
has, in essence, combined the two types as a single
factor, referred to as the DREF, the dose-rate
effectiveness factor. NCRP states that the DREF could
also be called a "dose-magnitude effectiveness factor"
(Ncrp80, p.9). A
DREF is the ratio of two linear slopes:
A steeper slope over a lower slope (Ncrp, p.176). The
significance of these slopes, demonstrated in the next
chapter, need not be considered for now.

NCRP gives a range for its DREF factors as 2 to 10
for human carcinogenesis by low-LET radiation. Thus,
if a human cancer-study provided cancer-risks per rad
from observations at very high doses, these risk-rates
would be divided by a factor of 2 to 10 to derive what
NCRP considers appropriate estimates for cancer-risk
per rad at low doses or low dose-rates.

Some users of DREFS refer to these very same
factors as 0.5 to 0.1. They are simply multiplying
the observed cancer-risks at high doses or high
dose-rates by 0.5 to 0.1 instead of dividing by 2 to 10.
The fractional formulation is in better accord with the
formal meaning of "factor," which is defined by Webster's
dictionary as "any of two or more quantities which
form a product when multiplied together."

The Premise of DREFS :

The underlying premise of DREFS is that human
dose-response for acute exposure is likely to have a
concave-upward shape, except at extremely high
doses. This premise is not only stated clearly in the
NCRP report, but also in UNSCEAR
1977 and ICRP 1977
(see Part 3 of this chapter).

Of course, readers have seen for themselves in
Chapters 13 and
14 that this premise is invalidated by
the A-Bomb Study (1950-1982), whose dose-response
has the opposite curve throughout the full dose-range.
And readers are reminded that when RERF analysts,
Shimizu and co-workers, examined all the A-bomb data
1956-1985, they too found the dose-response to be
either linear or supra-linear (see Chapter 14,
Part 2).
Even if data in subsequent follow-ups were to produce a
dose-response more linear than supra-linear, the
underlying premise of a concave-upward shape would
still be invalid.

Readers may wonder, "If the underlying premise of
reduction-factors has already been invalidated, then
why bother to discuss this topic at all?" Such a
question assumes that human evidence will be
accepted as the decisive reality-check on
expectations concerning humans.

Our position is that it should be. Therefore,
we are critical throughout this chapter whenever
human epidemiological evidence of good quality is
subordinated to non-human evidence.

Parts 2 and 3
of this chapter will show that
"the general wisdom" of DREFS first emerged in the
absence of good human epidemiological evidence, and
also that, for many years already, good human
evidence has been at variance with the underlying
premise of DREFS.

Some readers will find it intrinsically interesting to
see for themselves that, nonetheless, DREFS have
been overwhelmingly popular and well embraced in the
radiation community. This is demonstrated to mid-1989
by the statements provided in Part 3. Although we
focus, in Part 2, on only three of the DREF documents,
readers will find both earlier and later documents quoted
in Part 3. (The quotations in this chapter may not be
fully understood by readers who are unfamiliar with the
linear-quadratic hypothesis of dose-response in this
field. They may wish to study Chapter
23, Parts 1 and
2, before this chapter.)

In Chapter 23, we will show our own quantitative
approach to risk-estimation for acute-low doses and
for slow-low doses -- an approach which is
consistent with the existing human evidence.

We call attention to our emphasis above on low
doses: Acute-low and slow-low. As for high total
doses delivered slowly ("slow-high doses"),
this topic is explored separately in Part
6 of Chapter 23.

2. A Historical Perspective

Although good human evidence on the shape of
dose-response exists today, a couple of decades ago,
the human evidence was very thin on this issue. Some
animal experiments suggested that the dose-response
relationships for tumorigenesis and certain other
biological end-points were concave-upward, meaning
that the cancer-risk per rad (cGy) could be higher at
high doses than at low doses. If this were true for
humans, then it would mean that extrapolation from high
doses to low doses in a linear fashion would
overestimate the cancer-risk at low doses.

If one were to rely on some of the experimental
animal data, and assume the human dose-response
relationship to be concave-upward, then
reduction-factors would seem reasonable in trying to
assess cancer-risks at low doses. And this was done.
Over and over, one finds variants of the statement that
"Radiobiological reasons exist for making this
assumption in the absence of direct human data."
(Allusions to radiobiology are allusions to evidence from
other species and cell-studies, and to hypotheses
derived therefrom.)

But by 1980, when NCRP produced its widely cited
risk reduction-factors, human data were no longer
absent.

1980 -- What the Record Shows :

While the NCRP was preparing its 1980 report, its
colleagues in the radiation community were concurrently
preparing the BEIR-3 Report, with heavy reliance on the
A-Bomb Study 1950-1974
(TR-1-77; Bee77; Bee78). For the reasons
described in our Chapter 4, this is the
key study. With respect to the A-Bomb Study, NCRP
and BEIR-3 made five important admissions.

(1) Hiroshima -- Cancer Data :

As early as 1973, Baum (Baum73)
noted that there was evidence in some of the Hiroshima-Nagasaki data
for a decreasing slope for cancer-risk per cSv with
increasing dose -- just the opposite of what would be
expected from some of the animal data. The radiation
community suggested that the decreasing slope could
be ascribed to cell sterilization (or killing) at very high
doses.

In 1980, NCRP conceded that the effect was not
limited to very high doses: "Such an effect may be
seen at relatively low doses in the Hiroshima data"
(Ncrp80,
p.160). In other words, the A-Bomb Study was
warning that, in the human, the curve for cancer-risk
versus dose might be supra-linear throughout the
dose-range -- the opposite of the concave-upward
expectation.

Besides the concave-downward, supra-linear
curvature in the Hiroshima dose-response (just
mentioned), what were NCRP analysts able to see in
1980 ?

(2) Breast-Cancer Incidence :

In Ncrp80
(p.144, text and Table 10.3), the NCRP
authors also acknowledged that breast-cancer
incidence in the A-bomb survivors showed a
supra-linear dose-response (a highly significant
negative Q-coefficient in an L-Q model).

As we shall see below, BEIR-3 analysts were also
unable to find any support in the A-bomb evidence for
the concave-upward hypothesis.

(3) Nagasaki -- Cancer Incidence :

When the Nagasaki data for cancer-incidence were
examined alone, the dose-response for all cancers
combined (leukemia omitted) also warned against the
use of risk reduction-factors for acute doses: "In the
Nagasaki Tumor Registry data, the relationship between
the radiation dose and the total incidence of all major
cancers except leukemia is highly significant, and the
observed dose-response relationship appears linear,
with no suggestion of upward curvature"
(Beir80, p.181).

(4) Both Cities -- Cancer-Deaths :

When all cancers (leukemia omitted) in Hiroshima
and Nagasaki combined were analysed by BEIR-3,
using the LQ-L model (the solitary L for the linear
neutron-component), the dose-response was also
found to be linear. The Q-term was zero, as shown
in Beir80,
p.186, Table V-9, "Regression Analyses for
LSS Mortality Data, 1955-1974 (excluding Leukemia)."

In the fine print, one discovers that BEIR-3
constrained the equation so that the quadratic term
could not turn out negative. The Q term was
"constrained to be nonnegative"
(Beir80, p.186). We
have noted elsewhere in this book that a negative
Q-term means that a linear-quadratic model has a
supra-linear (concave-downward) shape. Thus,
when the BEIR-3 Committee constrained its equation
to produce a nonnegative Q-term, the Committee had
decided that a supra-linear dose-response must be
ruled out. With the constraint upon it, the quadratic
term turned out as zero -- the lowest value it could
be, without being negative.

(5) Leukemia Registry Data :

With respect to dose-response for human leukemia
in the A-bomb survivors, Beir80
gave enormous weight (as we shall see, in
Part 3) to its concave-upward
appearance in Nagasaki in the LSS sample. Because
leukemia is only a single cancer among many, the data
were exceedingly thin -- especially when Nagasaki was
examined alone. There were a total of 46 cases in all
Dose-Groups combined.

RERF analysts (Bee78,
p.198) had explicitly warned
that, "In the face of the paucity of cases (or deaths) in
the Nagasaki LSS sample in the low dose range, and
the suggestion that the dose-response pattern for the
entire Registry may be different, it would seem best not
to invest too heavily in the nonlinear appearance of the
LSS data."

By contrast, the Leukemia Registries for survivors
in both cities contained far more data
(Beir80, p.341). For
Nagasaki, the Registry increased the cases from 46
(in the LSS sample) to 231, and for Hiroshima, from 120
(in the LSS sample) to 323 cases. BEIR-3 itself showed
that the Registry data for leukemia were not
concave-upward in either Hiroshima or Nagasaki
(Beir80, p.343 Figure A-5).

Beside the A-Bomb Study :

The point is that, when the 1980
NCRP and BEIR-3
reports were issued, direct human data were certainly
no longer lacking on the shape of dose-response for
malignancies, and none of the data -- except the
inappropriate leukemia sample -- supported the
predicted concave-upward shape.

Indeed, NCRP itself described several minor human
studies, at low doses, in which dose-response appeared
concave-downward (Ncrp80,
pp.160-166). By the term "minor studies," we simply mean studies which
inherently lack the scientific power of the A-Bomb Study
(see Chapter 4). No disparagement of the work is
implied.

And with respect to induction of human
breast-cancer by low-LET radiation, there was already
a succession of studies additional to the A-Bomb Study.
Such studies pointed to a human dose-response which is linear,
not concave-upward (Boi77,
Boi79,
Land80,
My69,
Sho77. It is proper
to describe Land80 as an available analysis, because Land
was a member of the BEIR-3 Committee -- see Chapter 37).

Breast-cancer is one of the two most prominent
cancers in women (in the USA), and accounts for about
twenty percent of all their cancer-mortality, as already
noted in Chapter 21,
Part 3. There is every reason to
generalize from the breast-cancer data to
dose-response for less important cancer-sites, in the
absence of any contrary human evidence or contrary
logic.

1980 -- The Evidence Was Seen :

Whether one considers only the A-Bomb Study, or
additional studies too, the message from the direct
human data was that risk reduction-factors were a
mistake which would produce underestimates of
cancer-risk at low acute doses. The direct human data
were overwhelmingly suggesting linearity or
supra-linearity by 1980. And I was not alone in seeing it
(Go81). The record
above shows that the NCRP and
BEIR-3 radiation committees were seeing it too.

1980 -- Statement by NCRP :

Nonetheless, NCRP's 1980 report based DREFS on
animal experiments rather than the available human
epidemiology. NCRP explicitly admitted that its method
could provide "no rigorously-defensible approach to
deriving satisfactory DREFS for the human being"
(Ncrp80, p.2):

"Because of the complexity and wide spectrum of
the tumorigenic responses to radiation in the
experimental animal, however, there appears to be no
rigorously-defensible approach to deriving satisfactory
DREFS for the human being, for either single tumor
types or for all tumors collectively. Thus, the NCRP is
reluctant at this time to go beyond providing a range of
factors within which a single factor for the total yield of
tumors in man after exposure of the whole body would
probably lie. The DREF range is 2 to 10, when the
actual absorbed dose is 20 rads or less, or the dose rate
is 5 rads per year or less."

The tone of that statement suggests, to me, that
NCRP was not eager to defend its DREFS. And if a lack
of enthusiasm was present in NCRP's opening
statement, it would have been appropriate, in my
opinion. For in 1980 (Go81),
I was examining the very same 1950-1974 evidence from the A-Bomb Study
which NCRP had examined, and the evidence was
indeed badly at variance with NCRP's underlying
premise for DREFS -- namely, the premise of a
concave-upward dose-response in the human.

1980 -- Statement by BEIR :

As for BEIR-3, the Committee split in bitter dispute
over the shape of dose versus cancer-response in the
human, with Harald Rossi arguing against any linear
term at all, and for dominance of a quadratic term
(Beir80, pp.254-260),
and with the chairman, Edward Radford, arguing for a
linear model (Beir80, pp.227-253).

In the end, the 1979 Draft Report was replaced by a
compromise (Beir80,
p.190), in which the Committee
designated the linear-quadratic model (with a positive
Q-term) as its preferred basis for making
risk-estimates. (Details are in Part 3
of this chapter.) In other words, the human evidence was disregarded.
According to Edward Webster, BEIR-3 member:

"A linear-quadratic dose/effect relationship,
defensible in the light of current radiobiologic findings,
has been adopted by most of the Committee members
as a reasonable basis for prediction of risks of
radiation-induced cancer"
(Beir80, p.261).

1981 and 1983 -- Reduction-Factors Challenged :

Why Do Experts Disagree ?

By 1981, I reported that examination of the
Hiroshima-Nagasaki evidence seriously pointed to a
supra-linear relationship, between cancer-risk and dose
of low-LET radiation, throughout the dose-range
(Go81). This was the
shape which the BEIR-3 Committee had ruled out, by actively
constraining its equation (see above).

The finding in Go81
of supra-linearity, in agreement
with Baum's earlier finding, had the additional weight of
much more follow-up data since Baum's report.
Furthermore, there was no basis for ascribing the
supra-linearity to the presumed neutron-exposure at
Hiroshima (see Chapter 8,
Part 5).

People in and outside this field often ask, "Why do
you experts disagree?" But it is not at all clear that we
actually disagree about what the evidence is saying.
If the BEIR-3 Committee had not artificially constrained
its regression analysis (Table V-9), it probably would
have found exactly what I reported from the same data
in 1981 (Go81): A
supra-linear, concave-downward
dose-response for radiation carcinogenesis in the
human.

Of course, both supra-linearity and linearity are
incompatible with the use of risk reduction-factors for
acute-low and slow-low doses. So the independent
analysis in Go81
was a clear challenge to DREFS.

RERF Analysts Challenge DREFS :

In 1983, Wakabayashi and co-workers at RERF
attempted to address the dose-response relationship in
A-bomb survivors, by using cancer-incidence data for
Nagasaki. This choice was made because neutrons had
never been considered prominent in the Nagasaki dose.
These workers tried to compare a full quadratic model
(Q), a linear-quadratic model (LQ), and a pure linear
model (L) for the study of all cancers combined (omitting
leukemia) in the Nagasaki cancer-incidence data. We
quote the findings made by these workers directly
(Waka83,
pp.128-129). When they refer to "all cancers
except leukemia," they do not mean that leukemia is
different; they mean that leukemia is not part of the
analysis:

"The Q model does not fit the incidence data on all
cancers except leukemia, whereas the L and L-Q
models fit equally well. The linear term is significant in
the L-Q model, whereas the quadratic term is not. Thus
the linear model appears to be the better for all cancers
except leukemia. A similar tendency was observed for
several specific sites of cancer, i.e. cancers of the lung,
breast, thyroid, and stomach; the Q model either does
not fit (for breast cancer) or fits more poorly than the L
or L-Q model, and the quadratic term in the L-Q model
does not differ from zero (the calculated value is
negative). These findings, when compared with the
analysis of the fit of these models to cancer-mortality in
1950-1978, where the neutron component was also
considered, are seen to to be very similar.

"Thus it seems reasonable to use the linear model in
risk estimation in the present analysis, though we
cannot statistically distinguish one model from another
among these three alternatives except for
cancers other than leukemia and for
breast cancer [emphasis added]. In the dissenting
section in the BEIR III report, Rossi stated that the
dose-response for mortality from all cancers in
Nagasaki (1950-1974) fits a quadratic model best. The
present analysis does not support this. Rather, the data
suggest a linear model (see Radford's comments in the
same dissenting section) or at least a linear-quadratic
model, which the BEIR III Committee used as the basis
of risk estimation." (Parentheses are in the original.)

Another Clear Warning : So in 1983 -- only three
years after the NCRP and BEIR-3 reports of 1980 --
Wakabayashi and co-workers were clearly alerting the
radiation community (again) that for all cancers
combined, and for breast-cancer specifically, the linear
model fit best -- which meant that reduction-factors
rested on a fantasy, with respect to the human
evidence.

And in pointing out that the quadratic term in the L-Q
model was negative (though not provably significantly
so), they were alerting the radiation community (again)
that supra-linearity might be the case.

1985 -- Refusal To Abandon DREFS :

In 1985, the radiation community produced two new
reports on radiation risks: Nrc85
and Nih85. Both
reports endorsed the use of DREFS in extrapolating
from high acute to low acute doses, even though the
real-world human evidence was at variance with the
presumption on which the DREFS were based.

Exemptions from DREF-treatment have been made,
however, one cancer-site at a time. If human evidence
is conclusively against a concave-upward
dose-response for a particular kind of cancer, then
DREFS are no longer used by the radiation community
for that one site. Cancers of the breast and thyroid are
examples of such exceptions.

For instance, the report of the NIH Working Group
conceded that, for these two cancers, the linear model
fit the data best, but its authors still were clinging to the
concave-upward or linear-quadratic fit for all other
cancers, with associated DREFS
(Nih85, p.iv, p.55). In
the quotation below, PC refers to Probability of
Causation.

"In general, the Working Group has sought to use
the dose-effect model for each cancer which is most
consistent with both the human epidemiological data
and the radiobiological data. For leukemia, the data are
consistent with a so-called linear-quadratic model;
hence this model is the basis for the PC tables
calculated for leukemia. This model uses two constants
and, in general predicts that small doses of radiation
have a lesser effect per rad than do higher doses.
There are radiobiological reasons for assuming that a
linear-quadratic model is generally applicable to other
cancers, which are discussed both in the BEIR III report
and in Chapter III of the present report. Accordingly, we
have used this approach for all cancers except those of
the thyroid and breast. For carcinoma of the breast and
thyroid, the data appear to be best described by a
simple linear relationship in which the carcinogenic
effect of radiation is directly proportional to dose; again
the tables are based on this interpretation"
(Nih85, p.iv).

An Eight-Point Commentary :

I consider the statements above to be faulted
on several grounds:

(1) Human Evidence Disregarded :

Notwithstanding its claim of considering human
epidemiological evidence as well as radiobiological data,
the NIH report appears simply to disregard the findings
which show the linear fit to be best for all human
cancers combined, in both
Beir80 (p.186, Table V-9)
and in Waka83. The
report also disregards my own
1981 analysis, which was highly suggestive of a
supra-linear fit for all human cancers combined, in the
A-bomb survivor experience (Go81).

(2) Site-Specific Approach :

It is scientifically far better to use the findings based
on all cancers combined, than to subdivide the
observations by single sites of cancer. The NIH report
invites error by examining each cancer-site separately.
This approach creates the
small-numbers problem,
except for a very few common cancers. For all the other
cancer-sites, when analysts attempt to analyse the sites
one at a time, and the numbers pertaining to each are
inadequate for reliable analysis, then spurious results
are easily obtained.

(3) Leukemia Dose-Response :

The NIH Report rejected the data in the much larger
Hiroshima and Nagasaki Leukemia Registries. As noted
earlier in Part 2, those data do not fit the
linear-quadratic, concave-upward model best; they fit
the linear, or even the supra-linear model best. (See
"1980 -- What the Record Shows"
above; also Go81). It
is interesting to note that, in the A-Bomb Study, the
radiation community mounted a massive effort to revise
the dose-estimates (DS86), but the community has
made no meaningful effort to resolve the relatively minor
problems which inhibit full use of the data-rich
Leukemia Registries for both cities.

(4) Reasonable Presumption Rejected :

When all cancers combined (leukemia omitted) show
a dose-response which is not concave-upward
(Beir80,
Go81,
Waka83), and when two common types
of cancer (breast and thyroid), analyzed separately,
show a dose-response which is not concave-upward
(Nih85),
then the reasonable presumption is that the
other cancers would not show a concave-upward
dose-response either, if there were enough evidence to
be reliable. However, in opting for the site-by-site
approach, the NIH Working Group was rejecting the
reasonable presumption.

(5) A Question of Consistency :

Substituting for the reasonable presumption, the NIH
Working Group accepted "...radiobiological reasons for
assuming that the linear-quadratic model is generally
applicable to other cancers..."
(Nih85, p.iv). Facing a
choice between generalizing from strong, real-world
evidence directly from the human, versus generalizing
from other species and from their preferred
radiobiological hypothesis, the NIH Working Group
chose the latter -- and used risk reduction-factors.

The NIH Working Group appeared to require no
suitable human epidemiological evidence in order to
embrace a concept (the concave-upward
dose-response) which reduced risk-estimates, but
appeared to require a mountain of human
epidemiological evidence -- extending to each
cancer-site separately -- before embracing a concept
(the linear dose-response) which would mean higher
risk-estimates.

(6) "Not in Peoria!" :

Refusal by the NIH Working Group, to apply the
findings from all cancer-sites combined to the individual
cancer-sites, or from cancers of the breast and thyroid
to other sites, amounted to the "Not in Peoria"
response to evidence -- a response which we explained
and criticized earlier (Chapter 21,
Part 3). The Peoria
approach, with special DREF-exemptions for cancers of
the breast and thyroid, is found in additional reports
from the radiation community (see Part 3).

No rational explanation has been offered in such
reports for assuming that the shape of dose-response in
one cancer would differ from the shape in another
cancer -- an assumption which seems particularly
irrational when, within the existing evidence, the shape
is the same for thyroid-cancer, breast-cancer, and for
all cancer-sites combined.

(7) No Demand from Radiobiology :

As we will show in Chapter 23,
there was no reason for the NIH Working Group to have assumed that
"radiobiological reasons" demand or even suggest the
necessity of a concave-upward dose-response in the
human.

For decades, it had been understood that a
linear-quadratic equation can be modified away from a
concave-upward shape by an exponential modifier, and
that this should be done, if the modifier provides a better
fit to actual observations than the equation without such
a modifier. Indeed, the 1980 NCRP report itself is on
record as recognizing this fact
(Ncrp80, p.19, Figure
3.5).

However, it appears that the various radiation
committees did not feel obliged to use the actual human
observations. In the next chapter,
we shall demonstrate how the linear-quadratic model, even with positive
coefficients, can produce a curve which is
concave-downward (supra-linear) -- in accord with
the the actual observations.

(8) Rejection of Human Evidence :

The NIH Working Group appears to have rejected
the strong human evidence which was at variance with
risk reduction-factors.

I do not object because the NIH Working Group
appears to have paid no attention to my own work -- I
object because it appears to have paid little attention to
anyone's work if that work was in conflict with
DREFS.

3. The Exact Statements
Which Convert Myth into Consensus

We call the supposed propriety of using DREFs
"myth" because the practice is in conflict with good
human evidence. How a myth can become a general
consensus may be illuminated by the chronological
assembly of exact statements here about the
expected concave-upward ("linear-quadratic")
dose-response in humans and the consequent use of
reduction-factors in risk-estimation. Our phrase
above, "general consensus," is adapted from
entry #9 below.

As far as we know, this assembly of exact statements
has not been available before.

Readers will see that some of these reports attempt
to justify the use of risk reduction-factors, by prediction
from non-human data and radiobiology, and that the
rest simply quote the others as justification.

Although DREFS have spread throughout the
literature and will be found at every turn, their basis is
the same presumption stated by UNSCEAR and ICRP in
1977 -- a presumption which was invalidated in the
same year by the reality-check of direct human data
from the 1950-1974 A-Bomb Study
(TR-1-77;
Bee77).

The United Nations Scientific Committee on the
Effects of Atomic Radiation is UNSCEAR. Its individual
analysts are acknowledged in our Chapter 37. These
analysts addressed the topic of risk reduction-factors in
Un77, Annex G, p.366, para.34-36 as follows.

(para. 34): "Indeed, it has been suggested on
theoretical grounds and microdosimetric grounds, that
the tumour-inducing effect of radiation is likely to be
represented substantially by the sum of a linear term in
dose corresponding to the consequences of single
events due to ionization tracks passing through sensitive
cell structures, and of a quadratic term in (dose)^2
corresponding to damage due to two events. It must be
emphasized therefore that the frequency of tumours
induced per unit absorbed dose at a given dose level
applies strictly to that dose level, and that the likely
frequency per rad at low dose levels of a few rad or less,
which are of most concern in radiation protection,
cannot be assumed to be equal to the frequency
observed per unit absorbed dose at higher levels."

A little further on, making use of the linear-quadratic
relationship with `a' being the coefficient of the linear
term in dose and `b' being the coefficient of the
quadratic term in dose, UNSCEAR made some
projections of what might be the "risk-reduction" at low
doses. The authors then said the following:

"Data on the genetic effects of low-LET radiation in
the mouse and on the induction of chromosome
aberrations in several mammalian species including
man which have been analysed in this way suggest
values of b/a in the range of 0.01-0.03, and it has been
suggested that similar values may apply for
carcinogenesis. If this is so, it would indicate that
estimates of carcinogenic effects per rad derived at
doses of 100 rad of low-LET radiation could only
overestimate the frequency of effects per rad at low
dose by a factor of between 2 and 4."

A Strong Recommendation :

Later in its 1977 report, UNSCEAR strongly
recommended that risk reduction-factors be used.
Referring to its own central value of 1.0 per 10,000 per
rad for the Cancer-Yield (including leukemia), the
authors said (Un77, p.414, para.318):

"It is to be expected that low LET radiation is likely to
be less carcinogenic per unit absorbed dose at doses of
a few rads than at levels of one or a few hundred rads.
For dose levels at which a leukemia induction rate of
(15-25) 10^-6 rad^-1 may apply (see 1196), a ratio of
4-6 between the frequency of other induced fatal
malignancies and that for leukemia would imply a total
for all fatal induced malignancies, including leukemia, of
(5-7) times (15-25) 10^-6 rad^-1, suggesting a value of
about 100 10^-6 rad^-1 at such dose levels. It must be
emphasized again, however, that such a value is
derived from mortalities induced at doses in excess of
100 rad. The value appropriate to the much lower dose
levels involved in occupational exposure, and even more
so in environmental exposures to radiation, may well be
substantially less."

Basis -- An Assumption :

UNSCEAR's statements above ("... suggested on
theoretical grounds...", "If this is so ...") made it very
clear indeed that its suggestion of risk reduction-factors
was based on its assumption for humans of a
linear-quadratic dose-response (with a positive
coefficient for the quadratic term) -- in other words, the
assumption of a concave-upward dose-response. It
is self-evident that the UNSCEAR risk reduction-factors
of 2 to 4 (for going from high acute to low acute doses)
would not apply at all, if the concave-upward
dose-response relationship simply did not exist.

Subsequent information, published in 1977 and
thereafter, has shown that the human dose-response is
either concave-downward or possibly linear, not
concave-upward (see Part 2 of this chapter). The very
basis of that early UNSCEAR suggestion of 2 to 4 as
reduction-factors -- which was once reasonable
enough as a hypothesis -- has been totally undermined
by this later information.

Readers will see below what UNSCEAR had to say
on the topic in its 1986 report.

In January, 1977, the International Commission on
Radiological Protection (ICRP) adopted
"Recommendations" which were published that year as
ICRP Publication 26, in Annals of the ICRP (Icrp77).
The publication identifies the editor and scientific
secretary to have been Dr. F.D. Sowby, and the
chairman to have been Dr. C.G. Stewart, Atomic Energy
of Canada Ltd.

Paragraph 27 (p.6): "For radiation protection
purposes it is necessary to make certain simplifying
assumptions. One such basic assumption underlying
the Commission's recommendations is that, regarding
stochastic effects, there is, within the range of exposure
conditions usually encountered in radiation work, a
linear relationship without threshold between dose and
probability of effect."

Paragraph 28 (pp.6-7): "The added risk from a given
dose increment will depend on the slope of the
dose-response relationship. If the dose-response
relationship for stochastic processes is in fact highly
sigmoid, the risk from low doses could be overestimated
by making linear extrapolation from data obtained at
high doses. There are radiobiological grounds for
assuming that the dose-response curve for low-LET
radiation will generally increase in slope with increasing
dose and dose rate, over the absorbed dose range up to
a few gray. For many effects studied experimentally,
the response in this range can be represented by an
expression of the form: E = aD + bD^2, where E denotes
the effect, D the dose and `a' and `b' are constants.
[ICRP footnote: "At high doses this expression would
have to be modified to take account of the decreased
tumour risk caused by cell sterilization."] The quadratic
term (bD^2) in this expression predominates at high
absorbed doses (generally above one gray) and high
absorbed-dose rates (of the order of one gray per min);
however, the linear term (aD) and the slope that it
represents come to predominate as the dose and dose
rate are reduced. Although a relationship of this form
has been documented for a variety of effects, the
relative values of the parameters `a' and `b' vary from
one observation to another. The extent to which the
relationship may differ for other situations remains to be
determined. For human populations in particular,
knowledge of dose-response relationships is too limited
to enable confident prediction of the shapes and slopes
of the curves at low doses and low dose rates.
Nevertheless, in a few instances risk estimates can be
based on results of irradiation of human populations
involving single absorbed doses, of the order of 0.5 Gy
or less, or to such doses repeated at intervals of a few
days or more. In such cases it can be reasonably
assumed that the frequency per unit absorbed dose of
particular harmful effects resulting from such exposures
is not likely to overestimate greatly the frequency of
such effects in the dose range of concern in radiation
protection, even though the latter may be received at
much lower dose rates."

Paragraph 29 (p.7): "In many instances, however,
risk estimates depend on data derived from irradiation
involving higher doses delivered at high dose rates. In
these cases, it is likely that the frequency of effects per
unit dose will be lower following exposure to low doses
or to doses delivered at low dose rates, and it may be
appropriate, therefore, to reduce these estimates by a
factor to allow for the probable difference in risk. The
risk factors discussed later have therefore been chosen
as far as possible to apply in practice for the purposes of
radiation protection."

No Supporting Data Cited :

It is to be noted that ICRP Report 26 cites no
evidence, no studies, and no sources whatsoever for
any of its conclusions, and the report lacks even a list of
references. One can assume, however, that Paragraph
28 includes early reports from the fluoroscopy studies
cited in Chapter 21 of this book,
when that paragraph refers to risk-estimates based on "single absorbed
doses, of the order of 0.5 Gy or less, or to such doses
repeated at intervals of a few days or more."

The ICRP's 1977 position on reduction-factors was
interpreted as follows by Dr. Roger J. Berry, an ICRP
member in 1987 (Berry87, p.122):

"The Commission also decided that for
sparsely-ionizing radiations such as x- or gamma-rays
the necessary interpolation between effects observed at
high doses and those predicted at low doses ... should
have some allowance for non-linearity of
dose-response, with the vast majority of biological
evidence to date suggesting that the dose-response
would be concave-upwards."

Important Points Overlooked :

There are some important points made in the original
ICRP statements, which are not widely appreciated.

(A) The ICRP stated very clearly in its
Paragraph 28
that when the original estimates of risk are based upon
observations at a total dose of 0.5 Gy (50 rads), or at
higher doses which were fractionated into a series of
individual exposures below 50 rads, it is reasonable to
assume that no risk reduction-factors are appropriate
for the purpose of estimating "the frequency of such
effects [risks] in the dose-range of concern in radiation
protection."

(B) The ICRP was very clear in its
Paragraph 28 in
stating its uncertainty concerning the dose-response
relationship in humans at low doses and dose-rates.
What ICRP said was that, if a concave-upward
dose-response existed and if risk-estimates were
based on high doses delivered acutely, then risk
reduction-factors would be indicated in order to derive
risk-estimates for low-dose exposure.

One cannot disagree with this "if-then" position.
But in 1977, apparently the ICRP was still unaware that
the dose-response relationship in the 1950-74 A-Bomb
Study was not concave-upward, but was linear or
even concave-downward. The ICRP's own words
make it clear that, if ICRP had known the human
dose-response relationship was going to be linear or
concave-downward throughout the dose-range, when
enough data were in, ICRP would not have suggested
any risk-reduction factors at all, for extrapolations from
high acute to low acute doses.

In 1972, the BEIR-1 Committee had adopted the
linear model of dose-response for all cancers
(Beir72).
Its individual analysts are acknowledged in our Chapter 37.

By contrast, the BEIR-3 Committee was bitterly split
over its position on dose-response, as already noted in
Part 2 of this chapter. A
compromise subcommittee was established
(see Chapter 37), and in the end, the
linear-quadratic, concave-upward dose-response
was declared as the model "which most members of the
Committee prefer" for cancer-risk estimation
(Beir80,
p.190) -- (breast excepted, p.275, and thyroid
excepted, p.301).

Where did the 1980 BEIR-3 Committee obtain this
concave-upward curve, and a suitable equation, when
its own analysis of the A-bomb survivors showed no
positive Q-term at all in the linear-quadratic fit (see
Part 2 of this chapter) ? BEIR-3
replaced the linear dose-response which it found for
all cancers (Beir80,
p.186, Table V-9), by adapting the leukemia curve --
which showed the preferred shape (see Part 2). This
substitution is unmistakable in Beir80, pages 186-187,
250.

The record shows that the BEIR-3 Committee was
fully acquainted with the evidence showing that
dose-response for leukemia was also linear (not
concave-upward) when the Leukemia Registries were
used instead of the tiny LSS sample (Beir80, p.341,
p.343 - Figure A-5). Yet BEIR-3 chose to base its
preferred risk-estimates for all cancers on the curve
provided by the flimsy data for leukemia in the
Nagasaki LSS sample.

The record shows also that in trying to fit the data for
all cancers combined to the linear-quadratic model, the
BEIR-3 Committee placed an "active constraint" upon
the LQ equation so that the quadratic term could not
be negative (Beir80,
p.186). Constrained in this way,
the Q-term then turned out as zero -- the lowest
possible value without being negative (negative meaning
supra-linearity).

Thus BEIR-3 was left with only a linear term, and
this too was incompatible with reduction-factors for
estimating risk at acute-low or at slow-low doses.
However, BEIR-3's linear finding received little
attention after the report endorsed the "preferred"
concave-upward model.

These reports were discussed in Part 2 of this
chapter. Both of them made the assumption of a
concave-upward dose-response, and so both of
them supported the use of risk reduction-factors for
extrapolating from high acute doses to low doses.

In 1985, the (U.S.) Nuclear Regulatory Commission
published its NUREG/CR-4214 report on health effects
from a nuclear power accident (Nrc85). In May 1989,
the NRC issued a revised version of the same report
(Nrc89). In both versions, the section on
radiation-induced cancer was written by Ethel Gilbert,
an analyst at Battelle Pacific Northwest Laboratories.

This report addressed the issue of risk
reduction-factors, but introduced nothing at all in the
way of information concerning the issue. Instead,
without any critical analysis, the NRC Report simply
applied the mid-value of the range proposed by NCRP
in 1980. We quote a passage which is identical in both
the 1985 and 1989 versions:

"For most cancer-types, the central estimates are
obtained by modifying the linear risk estimates ... by the
factor 0.30 + 0.47D (where D is the dose in Gy),
resulting in a linear-quadratic function of dose. The
intent of using this factor is to account for the reduction
in effects likely to result from the low doses and dose
rates expected to be experienced by much of the
exposed population in a nuclear power plant accident.
The factor 0.3 is obtained as the midpoint of the range
0.1 to 0.5 suggested by NCRP (1980) ... "
(Nrc85,
p.II-99; Nrc89, p.II-125).

Appeal to Authority :

The range suggested by NCRP was indeed 0.1 to 0.5
(or 2 to 10). By citing Ncrp80,
the NRC Report was using the "appeal to authority" device, as if Ncrp80 had
presented a convincing scientific basis for the factors.
The NRC Report does not warn its readers that the
NCRP itself had warned that the reduction-factors (A)
were not based on human evidence, and (B) were not
"rigorously defensible" as satisfactory for humans
(Ncrp80, p.2).

The NRC Report simply copied NCRP in its use of a
linear-quadratic relationship (except for breast and
thyroid cancer). NRC provided no evidence for a
linear-quadratic relationship, and it demonstrated no
awareness of the considerable evidence already
available that the human dose-response for all cancers
combined was not concave-upward. By adopting the
linear-quadratic relationship (with an inferred positive
coefficient for the quadratic term), NRC was necessarily
assuming a concave-upward dose-response.

The NRC Report, adopting the "Not in Peoria"
approach like the NIH 1985
report, did concede the linear relationship for cancers of
the breast and thyroid. Referring to DREFS, the NRC Report
said: "Exceptions to the use of these reduction factors in
obtaining central estimates are breast and thyroid
cancer. For breast cancer, the non-age-specific linear
estimate is used without modification of the central estimate"
(Nrc85,
p.II-99). In the 1989 version, the first sentence has
been modified: "Exceptions to the use of these
reduction factors in obtaining central estimates are
breast cancer, thyroid cancer, and cancers resulting
from in utero exposure"
(Nrc89, p.II-125).

John S. Evans, of the Harvard School of Public
Health, was one of the three principal authors of the
1985 Nuclear Regulatory Report (Nrc85),
and he is also one of three co-authors of the article in the New
England Journal of Medicine (Sept. 25, 1986),
"The Influence of Diagnostic Radiography on the
Incidence of Breast Cancer and Leukemia" (Evans86). Not
surprisingly, the statements in the NEJM article
pertaining to risk reduction-factors are just like the
statements in Nrc85 and in
Ncrp80. We quote from
Evans86 (p.811). The parenthesis was in the original:

"Common approaches for extrapolating results to
low doses involve one of two assumptions. In some
types of cancer, low doses of radiation may be as
effective (per unit of dosage) as high doses in inducing
tumors. In others, low doses are perhaps only 1/10 to
1/2 as effective."

Thus, in two sentences, risk-reduction factors and
the Peoria approach to dose-response have been
conveyed to the medical community.

Building the Consensus :

A few paragraphs later, the authors speak
specifically of breast cancer: "The equation
describing the `central estimate' relies on the relative
risk projection method and includes only a linear term
because there is little evidence to suggest that the
risk is reduced at lower doses" (and they cite
Boice79;
Waka83;
Kato82;
Sho77). In other words,
like Nrc85,
Evans86
accepts the possibility that there
is no reduction factor for breast-cancer.

For leukemia, however, Evans86
"assumes that a low dose of radiation is 30 percent as effective (per
unit dosage) as a high dose in inducing leukemia"
(parenthesis in the original), and the authors cite
Gilbert (Nrc85) for support.

In summary, the assumptions of
Ncrp80
and Nrc85
with regard to risk-reduction factors have been
transmitted to the medical community. Nowhere in
Evans86
is there acknowledgment that the human
evidence for all cancers combined is totally at
variance with the statement that, for some cancers,
"... low doses are perhaps only 1/10 to 1/2 as
effective ..." as high doses.

UNSCEAR-86, in its summary on radiation
carcinogenesis, states (Un86, p.243, para.483):
"Recent experimental findings on radiation-induced
tumours in experimental animals have not substantially
changed the main conclusions reached in annex I of the
1977 UNSCEAR report. Most data support the notion
that dose-response relationships for x and gamma rays
tend to be curvilinear and concave upward at low doses.
Under these conditions, tumour induction is dose-rate
dependent, in that a reduction of the dose rate, or
fractionation, reduces the tumour yield. A linear
extrapolation of the risk from doses delivered at high
rates to zero dose would thus, as a rule, over-estimate
the real risk at low doses and dose rates."

And (p.243, para.485): "Having reviewed existing
data on dose-response relationships for
radiation-induced tumours in man, UNSCEAR considers
that this whole matter must be treated with caution
because at the present time observations are
fragmentary ... For sparsely-ionizing radiation, in some
cases (lung, thyroid, breast), the data available are
consistent with linear or linear-quadratic models ..."
Bone sarcoma is the only solid cancer for which
UNSCEAR-86 asserts that the linear model would
"definitely" overestimate the risk in humans
(p.243, para.486).

UNSCEAR takes a site-specific "Peoria" approach
to analysis, one organ at a time. Since of course there
is not a human database for each separate cancer with
the size and statistical power which comes from all
cancers combined in the A-Bomb Study, the
site-specific approach means that UNSCEAR is likely
to say, indefinitely and perhaps forever, that human
evidence is lacking at low doses. However, this lack is
quasi-artificial -- a result of insisting that each organ
be considered in isolation. In 1986, all cancers
combined in the A-Bomb Study (1950-1982) were
clearly showing (A) radiation-induced excess at a low
dose, and (B) a dose-response curve which was not
concave-upward.

"For radiation-induced cancers of other organs, only
experimental data are available. For sparsely-ionizing
radiations upward concave curvilinear dose-response
relationships with pronounced dose-rate and
fractionation effects are usually found. If similar curves
should apply to cancers in man, a linear extrapolation
of risk coefficients (obtained at the intermediate dose
region after acute irradiation) to the low dose and low
dose rates, would very likely over-estimate the real risk,
possibly by a factor up to 5."

Thus, UNSCEAR-86 becomes a recent source cited
by others (for instance, by Preston and Pierce in
TR-9-87 or
Pr87b, p.34,35,36) as possibly justifying
use of risk reduction-factors. The reduction-factors of
1.5 to 3.0 cited by Preston and Pierce come from
Un86,
p.191, para.153, as quoted below. The parentheses are
in the original. "10 mGy" is the same as 1.0 rad.

"The linear-quadratic model may be characterized
by the quotient of the induction constants (a1/a2), which
varies with the radiation quality and the specific
biological effect. For high-LET particles, this quotient is
so high that the contribution of the dose-squared term
may normally be neglected. The model then becomes
linear. For low-LET radiation (considering chromosomal
exchanges, mutations, and induction of some
malignancies) the a1/a2 quotient is between 0.5 and 1.5
Gy. The over-estimation of the probability of effects at
about 10 mGy from single-dose data at 1-2 Gy (acutely
delivered) by linear (as opposed to linear-quadratic)
extrapolation would vary from 1.5 to 3.0 for an assumed
reasonable set of parameters."

Readers may note that Un86
uses a1 and a2 as the coefficients for the linear and quadratic
terms, respectively, whereas other sources (including
Un77)
often use a and b for these coefficients. Also, readers
may be perplexed that Un86 gives the ratio (a1/a2) in
units of grays. This is done because the dose-units of
a1 (the linear coefficient) are Gy^-1, the units of a2 (the
quadratic coefficient) are Gy^-2. Therefore, on division
we have Gy^-1 / Gy^-2, which is 1 / Gy^-1. Since this
is the same as Gy, the ratio can be expressed in grays. This
is awkward, so we use an alternative in
Chapter 23,
Part 2.

UNSCEAR is suggesting that, for "some
malignancies," the dose at which the linear contribution
to cancer-induction equals that for the quadratic
contribution lies between 50 and 150 rads (0.5 and 1.5
Gy). We shall be returning in Chapter
23 to this issue of
potential doses at which the linear and quadratic
contributions to cancer may be equal, and to the issue
of how such information is appropriately used.

In June 1987, the (U.S.) Department of Energy (DOE)
published its estimates of the health consequences from
the explosion of the Chernobyl nuclear power plant in a
report DOE/ER-0332 (Doe87). On the issue of risk
reduction-factors, Doe87 says the following (Section
7.2.1, pages 7.3 and 7.4). Parentheses are in the
original:

"In the majority of epidemiologic studies, the excess
cancer-risk coefficients depend on data derived from
irradiation involving high doses delivered at high dose
rates. The frequency of effects per unit dose is lower
for exposures to low doses delivered at low dose rates.
The UNSCEAR (1977) considered it appropriate to
reduce these risk coefficients (and hence, risk
estimates) by a factor on the order of 2.5 to 3 to adjust
for the probable reduction in risk. Interpolation of risk
coefficients from the high dose level at which effects in
humans are observed down to zero has been done on a
linear basis to assess an upper estimate of risk ..."

"In its 1980 report, the BEIR Committee (NAS/NRC
1980) considered the effect of dose-rate on
dose-response relationships. For high-LET radiation,
some evidence shows that protraction of dose over time,
i.e., delivery of the same dose at lower rates, increases
the cancer risk per unit of dose. For low-LET radiation,
as encountered from the Chernobyl releases, human
data on chronic exposure at low dose rates is limited;
however, experimental data in animals strongly indicate
that a given dose of low-LET radiation would produce
fewer effects at low dose rates than at high dose rates.
A reduction factor of two to three has been considered
in the 1980 BEIR Report, based on both human and
animal data. However, evidence from all these studies
indicates that, for a single exposure to low absorbed
dose, e.g., between 0 and 0.2 Gy (0 and 20 rad), of
low-LET radiation delivered at any dose rate, and from
any total dose delivered at a dose rate of 0.05 Gy/yr (5
rad/yr) or less, dose-effect reduction factors are likely to
be between two and ten (NCRP 1980)."

In December 1988, when Doe87
was carried in abbreviated form by the journal Science, the
presumption of a linear-quadratic (concave-upward)
dose-response was presented as if it were scientifically
solid:

"For latent health effects such as fatal cancers and
genetic disorders, the scientific community has reached
general consensus on a model derived from a
linear-quadratic dose-risk relation ..."
(Ansp88, p.1515).

Donald Pierce, RERF analyst and co-author of
TR-9-87 and
TR-12-87, gave a paper in Paris in which
he was discussing risk-estimates based on the recent
follow-ups of the A-bomb survivors. In that paper,
Pierce had the following to say about extrapolation to
low doses (Pier87):

"A final element in risk estimation involves
extrapolation to low doses. There is a substantial body
of radiobiological theory which bears on this, and yet
there remains great uncertainty. The primary reason for
raising this here is to insure that the above discussion is
not misinterpreted as pertaining directly to low-dose
risks. The BEIR-III LQ-L model, which provided more
or less the central value in their `envelope' of low-dose
extrapolations, had the effect of dividing their linear
low-dose extrapolations by 2.25. A recent UNSCEAR
Report (1986), containing very useful discussion of
many aspects of radiogenic risk estimation, suggests
using a range of 1.5 to 3.0 in place of this factor. Work
in progress at RERF suggests that within the context of
LQ-L models the upper part of the range of 1.5 to 3.0
suggested in UNSCEAR-86 is quite inconsistent with
the RERF data. This should not be taken too strongly
however, since it depends entirely on the LQ-L
assumption and since there is a great deal of other
scientific information to be taken into account."

Dr. Pierce does not comment on the fragmentary
basis for the UNSCEAR 1986 factors, but he does point
out in a somewhat obscure manner that the upper range
of those projections is "quite inconsistent" with the
RERF data.

High-Dose Data Need Increase-Factors :

It is hard to see why he is discussing LQ-L models at
all, in view of the curve he presents in a figure in his
paper -- a curve which is far more consistent with
supra-linearity of dose-response. Indeed, in
TR-9-87
(pp.29-32), Pierce acknowledges that the A-Bomb
Study shows a non-linear dose-response which is
concave-downward (supra-linear) at high doses. Thus,
if high-dose data were used to make estimates at low
doses, risk increase-factors, not risk
reduction-factors, would be needed.

Preston and Pierce, co-authors of
TR-9-87 (Pr87b),
briefly mention DREFS or risk reduction factors as point
(ii) in presenting their own estimates of Lifetime Fatal
Cancer-Yields at low doses:

"To make such estimates requires a number of
assumptions, the most critical of which involve: (i)
extrapolation of the nonleukemia risks beyond the
current follow-up, especially for those individuals who
were young when exposed; and (ii) the method used for
extrapolation to relatively small doses from the range of
1-2 Sv" (Pr87b, p.34).

In Table 13-A of this book,
entries C3, C4, and C5
clearly show that there are direct observations in the
A-bomb survivors at 14.6, 40.6, and 74.2 cSv
(Dose-Groups 3, 4, and 5, in the DS86 dosimetry). It is
utterly perplexing why RERF analysts are still discussing
extrapolations downward from doses like 100-200 cSv.
Not only are such extrapolations unnecessary, but the
high-dose observations suffer from the small-numbers
problem and are inherently less reliable than the
lower-dose observations. Indeed, we combined
Dose-Groups 6, 7, and 8 for that reason.

Preston and Pierce continue (in the same
paragraph): "Regarding point (ii), it is suggested in a
recent UNSCEAR report (Annex B, paragraph 153) that
linear extrapolation in this setting will overestimate
low-dose risks by a factor of 1.5 to 3.0. This is a major
source of uncertainty which must remain in the following
calculations" (Pr87b,
p.34. Parentheses are in the original).

The last statement suggests that the authors had
some reservations about the goodness of the UNSCEAR
estimate of risk reduction-factors, and if so, such
reservations would be in line with Pierce's statement
quoted above (Pier87)
that there was real inconsistency
of Un86's factor of 3 with the RERF data.

The inconsistency is glaring. Readers are referred
back to Chapter 14,
Part 2, where we quoted from
TR-12-87
(Shi87,
p.28-30). The authors of that report
-- and both Preston and Pierce are co-authors -- find
that dose-response in the DS86 sub-cohort is linear or
supra-linear -- not concave-upward.

Power of Persistence :

Nonetheless, in their tabulation of Lifetime Fatal
Cancer-Yields, Preston and Pierce displayed their linear
estimates and then showed reduction by factors of 1.5
and 3.0. Their tabulation is reproduced below (from
Pr87b, p.35):

The tabulation above demonstrates the power of risk
reduction-factors to persist in the radiation community
and in the literature (A) despite the absence of any need
for extrapolation from high to low doses -- since direct
human observations exist at low doses, and (B) despite
the presence of human evidence which invalidates the
key premise on which the factors rest -- namely, a
concave-upward dose-response.

When TR-9-87 appeared
in its abbreviated form in the journal Radiation Research
(Pr88), the use of
reduction-factors upon linear values was demonstrated
again -- apparently for the purpose of facilitating
comparisons with BEIR-3 and UNSCEAR.

(We use the linear risk-value from
Pr88 in our
Chapter 24,
Part 7. It is much lower
than the linear value for RBE 10 shown above. We have made no
error. Readers were warned in our Chapter
4 that the full RERF report and the abbreviated version
are not the same on this key matter.)

Early in its 1988 report, UNSCEAR announces that
some human evidence has developed to support the
use of risk reduction-factors for slow delivery of
low-LET radiation (Un88, p.34, para.208):

"The Committee concluded in 1986 that for some
tumours, i.e., carcinomas of the female breast and
perhaps of the thyroid a linear relationship at low and
intermediate doses of low-LET radiations gave a good
fit; for others a linear fit could not be rejected
statistically but other models, e.g., linear quadratic and
quadratic approximated the data equally well. These
observations are still assumed to be basically correct,
however, evidence presented recently to the Committee
suggests that fractionated doses at very low doses per
fraction may be less effective in inducing breast cancer
than deduced previously from the linear relationship and
apparent lack of dose-fractionation effects. [We are
splitting the Un88 paragraph here.]

"Recent epidemiological studies on patients
administered 131-iodine-iodides for diagnostic
purposes suggest that low-LET radiation at low dose
rates is also significantly less effective than intermediate
and high doses delivered at high dose rates. This
means probably that the dose-response relationship for
induction of cancer of the thyroid gland is also
non-linear (upward concave) as was suspected in the
UNSCEAR 1986 Report" (Un88,
p.34, para.208).

The breast-cancer study to which
Un88 is referring is
the Canadian Fluoroscopy Study as reported by
Howe in
1984. The radio-iodine studies to which Un88 is
referring are the studies in Sweden by Holm and
co-workers (Holm80,
Holm88).

UNSCEAR-88 presents the Holm studies as human
evidence supportive for a risk reduction-factor of at
least 3 and possibly even 4 for slow delivery
(Un88, p.491, para.604).

And UNSCEAR-88 presents the Howe report as
human evidence supportive for a risk reduction-factor of
at least 3 for low dose or low dose-rate
(Un88, p.492, para.605).

Then UNSCEAR-88 concludes its summary on
"Risks at Low Doses and Low Dose Rates" as follows
(p.492, para.607):

"From examination of both experimental and human
data the Committee concludes that the carcinogenic
effects of low-LET radiation are generally smaller at low
doses and at low dose rates compared with those at
high doses and dose rates. The reduction factors will
vary with dose and dose rate and with organ system but
will generally fall within the range 2 to 10."

Readers will recognize, of course, the familiar "two
to ten" range first suggested by NCRP in 1980. It was
based almost exclusively on non-human data. When
UNSCEAR-88 now adds the allusion to human
evidence, Un88 is
relying very heavily on the "recent" Howe and Holm studies.

Because the issue of risk reduction-factors is of such
importance, we will examine the
Howe Study (and its
1989 up-date) in Part 4 of this
chapter, and then the 1988
Holm Study in Part 5 of this chapter.

4. Unwarranted Conclusions
from the Canadian Fluoroscopy Study

As we explained in Chapter 21,
Part 1, the Canadian
Fluoroscopy Study consists of two distinct series: The
Nova Scotia women (number 1
in Chapter 21) versus the
other-Canadian women (number 4 in
Chapter 21). The Nova Scotia
series is distinct in at least two ways. First, the
total breast-dose accumulated was much higher, and
second, the per-rad risk appears higher
than in the other-Canadian series.

UNSCEAR-88, as noted in our
Part 3 above, is suggesting
that the lower per-rad risk in the other-Canadian
series (Howe84)
is supportive evidence for a dose-rate effect.

In at least three separate places,
Un88 cites the
conclusion by Howe
1984 that the dose-response in the Canadian
Fluoroscopy Study is either linear-quadratic or
quadratic -- in other words, concave-upward (Un88,
p.439, para.241; p.455, para.361; p.456, para.367).

The next year, November 1989, an up-date of the
Canadian Fluoroscopy Study was published
(Miller 1989) on
which Howe was a co-author. In the up-date, the
authors now disagree with the statement which is so
important to UNSCEAR-88. In
Mi89, the authors state (Mi89, p.1287):

"... the evidence from Table 2 indicates that the most
appropriate form of dose-response relation is a simple
linear one, with different slopes for Nova Scotia and the
other provinces ... For these models there was no
evidence of any upward curvature in the dose-response
relation (i.e., the addition of a quadratic term did not
significantly improve the fit ...).

We are not in any position to make an independent
evaluation of the dose-response relationship in the
Canadian Study. We would need raw data before their
reduction, and these data are not published.

What needs emphasis is that UNSCEAR's statement
is now in conflict with the more recent statement by
the study's own authors.

UNSCEAR-88, in the search
for human evidence to support its recommendation of risk
reduction-factors for slowly delivered doses, suggests that
the lower per-rad risk in the other-Canadian series compared with the
Nova Scotia series is due to a 20-fold lower dose-rate
per exposure for the other-Canadian series:

"In Nova Scotia, the patients were examined in the
anterior-posterior position (facing the x-ray tube)
whereas in the other provinces the patients were mainly
examined in the reverse position, resulting in doses per
fraction about 20 times smaller"
(Un88, p.456, para.367).

Miller, Howe and co-workers make a similar
comment in their discussion-section
(Mi89, p.1288):
"The only substantial difference in the dose-estimation
procedures for Nova Scotia and the other provinces was
in the proportion of women who faced the x-ray source.
This difference is well established, and even varying the
proportions substantially does not eliminate the
difference in the slopes. One possible biologic reason
for this difference is a dose-rate effect. Although the
mean numbers of fluoroscopic exposures were similar,
the rate per unit dose was more than an order of
magnitude greater in Nova Scotia than in the other
provinces."

Unwarranted Conclusions :

Both Un88 and
Mi89 are mistaken in their
conclusions that a dose-rate difference up to 20-fold
exists between the Nova Scotia series and the
other-Canadian series. In reality, the biologically
relevant rate at which total doses were accumulated in
the two series was not even two-fold apart.

Readers are referred back to Chapter
21, Part 1,
Study 3 (Massachusetts
Fluoroscopy). There, we showed that the average
delivery-rate of the rads in that
study -- which is the same as the other-Canadian
series, Study 4 -- is
about 4.6 rads at one time. The average delivery-rate
of the rads in the Nova Scotia
series is about 7.5 rads at one time. The ratio of
delivery-rates is (7.5 / 4.6), or 1.63 -- far below a factor
of 20. This finding is due to the fact that only a very
small fraction (about 13 %) of the total rads received in
the other-Canadian series was received at the low
dose-rate of 0.261 rad per exam.

Table 21-A provides a
convenient way to compare all
three fluoroscopy studies, not only in delivery-rate of
the rads at one time, but in the tracks-per-nucleus at
one time. In the Nova Scotia series, the
tracks-per-nucleus are 10.0335 compared with 6.1539
in the other-Canadian series.

In other words, there is no meaningful difference in
dose-rate between the studies.

Moreover, at such low doses and track-rates, the
quadratic term (for inter-track carcinogenesis) is just
negligible -- as is generally acknowledged -- and as is
illustrated in our Chapter 23,
Part 7. Thus, there is not
even a basis in principle for invoking a dose-rate effect
to explain the different slopes or per-rad risks in the
Nova Scotia versus other-Canadian series.

In any case, we have shown that no appreciable
difference in dose-rate exists between the two series.
Thus, the Canadian Fluoroscopy Study provides no
human evidence supportive of a dose-rate effect.

5. Unwarranted Conclusions
from the Holm Radio-Iodine Study

We are going to give some close attention here to a
particular study of patients who received diagnostic
radio-iodine, because the study has been recently
featured by the 1988 UNSCEAR Committee as
important human evidence supportive of a dose-rate
effect (Un88,
p.34, para.208, and p.459, para.389, and
p.491, para.602, 604).

The study is "Thyroid Cancer after Diagnostic Doses
of Iodine-131: A Retrospective Cohort Study," by Holm
and eleven co-workers, published in the (U.S.)
Journal of the National Cancer Institute,
September 21, 1988
(Holm88). A
preliminary report on
a small fraction of the study-sample was published in
1980 (Holm80a,
Holm80b).

The 1988 report states in its abstract, "Overall, these
data provide little proof that I-131 is carcinogenic in
humans and support the notion that the carcinogenic
potential of internal I-131 beta particles might be as low
as four times less than external x rays or gamma rays"
(Holm88, p.1132). The
same report states in its closing discussion, "... I-131
did not increase thyroid cancer risk in this cohort ..."
(Holm88, p.1137).

This is the message which is used by others as
human evidence supporting a safe-dose or at least a
greatly reduced risk if exposure is gradual rather than
acute. (A single dose of Iodine-131 decays gradually,
and does not deliver its total dose to the thyroid all at
one instant.)

As noted above, the 1988 UNSCEAR Committee
features the Holm Study as important human evidence
supporting the Committee's decision to recommend
large risk-reduction factors, for radiation doses which
are slowly delivered. Individual authors of the 1988
UNSCEAR Report are acknowledged in our Chapter 37. Lars-Erik
Holm is among them.

Edward Webster, also a member of the 1988
UNSCEAR Committee (and a key member of the
BEIR-3 Committee), features the 1980 Holm Study in
the course of claiming that the cancer-consequences
from Chernobyl will probably be small (see our
Chapter 24,
Part 9). Webster
says (Webs87, p.424): "The effect
of protraction [slow delivery of dose] may be the reason
why iodine-131 has been judged to be three times less
effective as a carcinogen per unit dose than x-rays
delivered at high dose rates (Ncrp85, Table 11.3). This
conservative judgment was largely based on the
investigation by Holm et al (Holm80a) which found no
excess thyroid cancer in 10,000 patients who had
received gland doses between 58 rem (adults) and 159
rems (persons aged less than 20) after an 18-year
follow-up."

Rosalyn Yalow, a co-author of the 1985 NIH Report
on radiation risk (Nih85),
also features Holm80a and
Holm88 in a 1989 discussion
of "radiation phobia" (Ya89,
p.160): "Let us consider first what we know
about the importance of dose-rate effects in
radiation-induced malignancy for any given cumulative
dose ... The relevant human evidence depends in part
on the use of iodine-131 for diagnosis of thyroid disease
and for the treatment of hyperthyroidism. Although only
a small fraction of the more than one million patients
who had I-131 uptake studies 20 or more years ago and
received 50-100 rem thyroidal doses have [sic] been
studied, no increase in thyroid cancer has been
observed in this group (Holm80a; Holm88). Only 5 % of
the more than 35,000 patients evaluated were less than
20 at the time of examination. These authors concluded
(Holm80a) that the carcinogenic potential of I-131 would
be fourfold less than would result from equivalent
externally administered x- or gamma-ray exposure."

Reality -- An Epidemic of Thyroid Cancer :

In great contrast to the above statements -- which
claim that no excess thyroid-cancer occurred in the
Holm Study and therefore the slow delivery of dose from
iodine-131 must account for this unexpected result -- it
turns out (1) that a huge excess of thyroid-cancer
occurred in the Holm Study, and (2) that the results of
the study have not been clearly revealed.

Because the huge excess is revealed only indirectly
in the 1988 Holm Study (half of one sentence, on page
1134 of Holm88),
we had to go through a series of
calculations to evaluate it. Before going through the
steps with the reader, we must first describe the nature
of the study.

Nature of the Holm Study :

The study-population consists of 38,653 patients (79
% females) who "were examined with diagnostic doses
of iodine-131" between 1951 and 1969. These patients
were "recruited from seven oncologic centers in
Sweden ..." Twenty-nine percent were examined in the
period 1951-1959, and 71 % in the period 1960-1969.

Age at the time of first I-131 examination ranged
from one to 74 years, with a mean age of 44 years for
the females and 46 years for the males. Only five
percent of the total cohort was below age 20 at the time
of examination.

One can certainly not assume that this is a
study-population which will be just like the general
population in risk of thyroid-cancer, except for its
radiation-dose from I-131.

Far from it. People with histories of thyroid
abnormalities such as enlarged (hyperplastic) thyroid,
goiter, or history of thyroid nodules, go on to show a rate
of thyroid-cancer enormously higher than patients without
such conditions (Pre87,
Table 2; McTier84,
p.581; Ron87,
p.4). By contrast, the evidence on
hyperthyroidism as a risk-factor is inconclusive.
McTier84 and Ron87 report finding no basis for calling it
a risk-factor. With regard to hypothyroidism, McTier84
shows suggestive evidence in a case-control study that
people with hypothyroidism may have a lower risk of
thyroid-cancer than people without hypothyroidism
(Relative Risk = 0.40 in Table 6, McTier84), but she
concludes: "In this study, a history of hypothyroidism
was not associated with an altered risk of developing
thyroid cancer" (McTier84, p.580).

In the Holm Study, mean radiation dose to the thyroid
from the I-131 was estimated to be about 0.5 Gy or 50
rads (Holm88,
p.1136). We independently checked this
estimate of mean dose, by starting with microcuries of
administered iodine-131, the mean weight of the gland,
and the 24-hour uptake. We arrived at an estimate of
52 rads, in very good agreement with the estimate in
Holm88. Holm and co-workers note that the distribution
of doses was not random among the patients: "...
patients who were examined for a suspected thyroid
tumor received higher I-131 activities per examination
than did others" (Holm88, p.1135). We shall return to
this later.

"The follow-up period lasted from the time of the
first I-131 examination until the date of diagnosis of
thyroid cancer, the date of emigration or death, or
December 31, 1984" (Holm88,
p.1134). The mean follow-up was 20 years (p.1134).

"The cohort was matched against the nationwide
Swedish Cancer Register (SCR) to identify malignant
thyroid tumors occurring between 1958 and 1984. The
SCR was started in 1958 and receives notifications on
diagnosed cancers from pathologists/cytologists and
clinicians ... The completeness of registration of thyroid
cancers is higher than 97 % ..."
(Holm88, p.1134).

Holm and co-workers assume that about 33 % of all
the patients "had some sort of thyroid treatment at
some time after the I-131 examination"
(Holm88,
p.1137). They specifically include thyroid surgery and
thyroid hormone medication among the likely
treatments.

Unabridged Results :

"Within 5 years of follow-up, each of 136 patients
had a thyroid cancer diagnosed, and an additional 3,443
patients died" (Holm88,
p.1134). This is the only
mention in the entire report of what happened during the
first five years after the exposure.

Beyond 5 years, 50 (total) additional
thyroid-cancers were observed by December 31, 1984
(Holm88,
p.1134, and Tables 4, 5, 7). Of these 50
additional cases, 34 occurred in the patients whose
initial exam was due to suspicion of thyroid cancer. The
Holm Study provides no way of knowing what fraction of
the 136 early cancers came from this initially suspect
group.

The figures above mean that at least 186
thyroid-cancers (136 + 50) were found in this
study-population. We say "at least" for a reason. The
number was assuredly greater than 186.

We must add some cases for the following reason.
Holm and co-workers state (Holm88,
p.1134) that "Thyroid cancers occurring between 1951 and 1957
could not be identified because of the lack of nationwide
incidence data." And from the previous page, we know
that 29 % of the 38,653 patients were examined in the
1951-1959 period. This means that all thyroid-cancers
occurring in this segment (11,209 patients) before 1958
were missed. It also means that there were fewer than
38,653 patients in the base-population which gave rise
to the 136 cases which were not missed during the first
five years of the follow-up. We surely will not
overestimate total cases if we add only 20 cases to the
136 observed within the first five years of follow-up.

Thus, a very reasonable approximation is that the
number of post-irradiation thyroid cancers observed in
38,653 patients was: 136 + 20 + 50 = 206 cases, during
a mean follow-up time (starting with the initial
iodine-131 exam) of 20 years.

Was this an excess?

Observation of a Huge Excess :

Holm and co-workers say, "The expected numbers
of malignant thyroid tumors were calculated by direct
standardization; adjustment was made for age- (in 5-yr
groups), sex-, and calendar year-specific cancer
incidence rates for the whole country obtained from the
SCR [Swedish Cancer Register] between 1958 and
1984" (Holm88, p.1134).

On this basis, they provide 39.4 as the expected
number of thyroid cancers during the follow-up
beyond the first five years. This expectation applies to
the 35,074 persons still in the study as the sixth year
begins (of the 38,653 initial patients, 3,443 have died,
and 136 with identified thyroid-cancers have been
dropped from follow-up). However, Holm and
co-workers do not tell what the expected number was
during the first five years of follow-up. Therefore, on
this crucial issue, we will have to make an estimate on
our own. It is surprising that the peer-reviewers of this
article did not insist on it.

As an approximation, we will assume that the
expected incidence rate (39.4 cases per 35,074
persons) in the sixth through 20th year of follow-up will
also apply to the first through fifth follow-up years. In
the U.S., the incidence of thyroid cancer in women is flat
from forty years of age onward through 80 years of age
(Beir80, p.167),
and we will use this for Sweden too.

A rate of (39.4 cancers per 35,074 persons during 15
years) is an average of (2.63 cases per 35,074 persons
each year). Adjusting the cancers for the larger
population during the first five years, we have (2.63
cancers) x (38,653 / 35,074), or (2.9 cancers per 38,653
persons each year). Finally, multiplying by 5 years, we
have an expectation during the first 5 years of about
14.5 cancers. We can call it 14.

But the observation during the first 5 years was
about 156 cases. The ratio of observed over expected
is (156 / 14), which means a rate some 11-fold above
normal.

When we compare the O / E ratio (observed over
expected) for the entire 20 years, we have:

In other words, there is a huge excess of thyroid
cancer in the patients who received the diagnostic
radio-iodine. Readers of the Holm Study learn nothing
about this.

What Became of the Excess ?

The Holm Study was undertaken by oncology centers
to find out if their diagnostic use of radio-iodine is
causing excess thyroid-cancer, and if it is, to estimate
the magnitude of the elevated risk.

However, no effort was made to establish the
expected rate from a control group having comparable
thyroid conditions except for the exposure to
Iodine-131. Instead, a predictably inappropriate control
group -- the general population -- was used. By
comparison with this inappropriate control group, a huge
excess of thyroid-cancer was observed in the
radio-iodine patients (an excess which the Holm Study
does not evaluate or discuss at all).

This finding is handled in the Holm Study not by
throwing out the 31 % of the sample suspected at the
outset of thyroid tumor, and not by trying to establish a
true expected rate for the remaining 69 % of the study
population. The excess is not even mentioned. Instead:

"In the calculations of person-years at risk, the first
5 years after the initial I-131 administration were
excluded for each patient. This was done to reduce the
possibility of cancer being present but not diagnosed at
the time of the examination and not detected clinically
until some years later. All thyroid cancers occurring
during the first 5 years after the initial iodine-131
examination were also excluded from the analyses for
the same reason" (Holm88, p.1134).

This approach reduced 206 cancers to 50. Since
Holm and co-workers used an expectation of 39.4, they
report (50 / 39.4), or 1.27 as the Standardized Incidence
Ratio (SIR), with a 95 % confidence interval of 0.94 to
1.67. In other words, with the 5-year exclusion, the
excess is not provably different from zero.

With the 5-year exclusion, the following details are
reported:

In the patients younger than 20 years old during the
exam, 2 thyroid cancers were observed. The SIR was
2.02, with a confidence interval of 0.24 to 7.22. In the
patients who received radio-iodine because of
suspicion of a thyroid tumor, the SIR was 2.77, with a 95
% confidence interval of 1.92 to 3.87. In the initially
non-suspect patients, the SIR was 0.62 (0.35 to 1.00).

The Holm Study also explores the effect of throwing
away the first ten years of results. This reduces the
206 cancers to 27, and the overall SIR to 0.93. Of the
27 remaining cases, 19 are in the group examined
because of suspicion of thyroid tumor, and their SIR is
2.17.

A Fatally Flawed Study :

The Control Group :

The Holm Study relies on a control-group which may
supply utterly inappropriate expected values, both for
the initially suspect group and for the initially
non-suspect group of thyroid patients. If the expected
values are inappropriate, this would make all the risk
ratios (Standard Incidence Ratios) and all the
conclusions therefrom misleading, at best.

It seems self-evident that no one can possibly know,
from the Holm Study, how much of the observed excess
cancer in the initially suspect group is due to the
radio-iodine and how much is due to the patients'
pre-radio-iodine condition. To say that none of the
excess is due to the radiation would require some
evidence. To say that all of the excess is due to
radiation would certainly be foolish, too, in view of the
higher risk of thyroid-cancer among patients suspected
of thyroid-cancer.

Nor does the Holm Study provide a basis for
confidence that the general population is an appropriate
control group for the initially non-suspect group. On
the contrary. The finding by
Holm88 (p.1135) that the
risk-ratio is only 0.62, after the 5-year exclusion,
strongly suggests that the "natural" risk (meaning,
without radio-iodine experience) of thyroid-cancer in
this special population of people with thyroid disorders,
may be a lot lower than the natural risk in the general
population.

Treatments Post-Radio-Iodine :

Moreover, no one can evaluate the impact, on the
study's outcome, of post-radio-iodine treatments
(including thyroid removal and thyroid hormones)
received by an estimated one-third of the 35,000
patients in the study-population. UNSCEAR 1986,
referring to the smaller Holm Study of 1980, rejects such
post-radio-iodine treatments as a likely contributor to
the study's presumed deficit of cancers
(Un86, p.229,
para.397). In 1988, Holm and co-workers dismiss this
problem with a single sentence: "The absence of any
increased thyroid cancer risk was considered not to be
ascribable to the thyroid treatment"
(Holm88, p.1137).
Their allusion to the absence of excess risk is, of
course, to an absence after the first five years of
results have been thrown away. Then the risk ratio
becomes 1.27, which is not provably different from 1.00
under the circumstances.

Diseases in the Studied Organ :

It is interesting that the 1986 UNSCEAR Report, in
listing several reasons for the claimed shortage of
excess cancers in the overall preliminary (1980) results,
points out that "... the subjects are a selected unhealthy
population, with a high percentage of thyroid
involvement, to whom specific rates of thyroid cancer
induction, valid in the general population, may not
apply" (Un86, p.229,
para.397).

Such insights about the fatal flaws of the Holm Study
seem to be discarded, however, in the 1988 UNSCEAR
Report (Un88). Un88
relies heavily on the Holm Study
on the key issue of risk reduction-factors.

Unknown Latency Period :

Another confounding variable in the Holm Study, not
mentioned by UNSCEAR, is the real possibility that
thyroid diseases themselves alter the latency period for
radiation-induced cancer. For instance, one or another
condition might induce promotional agents not present
in healthy thyroid cells, and the peak incidence of
radiation-induced cancer might occur 3, 5, or 8 years
post-irradiation. Such early peaking is well-observed
for radiation-induced leukemia, about 7.5 years after
exposure.

Pre-Judgments versus Inquiry :

Throwing out the observed excess, in 5-year or
10-year stages, is no solution whatsoever to these very
serious confounding variables. Throwing away any part
of such a follow-up reflects an unwarranted
pre-judgment, not a scientific inquiry, in our opinion.

We remind readers that the Holm Study is examining
a study-population which -- during the first five years of
follow-up -- showed an 11-fold excess of the exact
variable (thyroid-cancer) which the investigators were
hoping to study (see "Unabridged Results," above).

As an independent analyst, I cannot just pretend to
myself that this is a normal population showing
normal behavior during a latency period, and that if I
throw away these startling results, I can tell myself that I
have a normal population entering the sixth year of a
radiation follow-up study. It would really require some
supernatural omniscience on my part to decide that
truth would be best served by not mentioning the
11-fold excess and by throwing away the first five years
of results.

Nonetheless, I am unaware that any other analysts,
peer-reviewers, or radiation committees have (1) asked
for an explanation of the 3.9-fold higher rate of
thyroid-cancer in the exposed group (unabridged
results), or (2) challenged use of the general population
as a control group for this very abnormal
study-population, or (3) challenged the failure even to
divulge just how very abnormal the study-population is
-- e.g., an 11-fold excess rate of thyroid-cancer during
the first five years of follow-up, or (4) challenged the
throwing out of the first five years of the results. What I
think I see, so far, is an uncritical rush to embrace
this fatally flawed study with its welcome (welcome
to me, also) but unwarranted conclusions.

Consistency in Standards ?

Radio-iodine studies have also tested consistency
regarding reliance on human versus non-human
evidence. This chapter has shown, with regard to risk
reduction-factors (DREFS), how much of the radiation
community greatly prefers to generalize from the
non-human evidence than to generalize from the
human evidence.

However, in 1982, Lee and co-workers published a
rat-study in which they found no lesser carcinogenicity
of slow doses from iodine-131 compared with acute
doses from 250 kVp X-rays, and the study extended
down to thyroid doses of 80 rads
(Lee82). Clearly, this
finding is not as welcome as lesser carcinogenicity
from iodine-131 would be.

"Iodine-131 has frequently been used to induce
tumors in experimental animals, although its
effectiveness relative to external photon exposures has
been studied only to a limited extent. Earlier studies
with high doses to the thyroid gland suggested that
iodine-131 was one-tenth to one-fourth as effective
as x rays in producing thyroid tumors. Lee et al.
observed that with lower doses the difference in
effectiveness between the two types of radiation was
less pronounced and perhaps even the same at doses
less than 3-4 Gy. [We are splitting the
Holm88
paragraph here.]

"Like many other experiments on animals, their
results are limited by the fact that iodine-131 is an
efficient cancer inducer in certain animal species and
strains only, such as the CBA mice and the Long-Evans
rats. Lee et al. used female Long-Evans rats in their
study, and the results may well have differed had they
used male rats or a mixture of the two sexes.
Regardless, there is a great deal of uncertainty in
extrapolation from animal data to human populations.
Epidemiologic data are therefore the preferred source of
information for obtaining risk estimates in humans"
(Holm88, p.1135).

We agree. But we would say "appropriate
epidemiologic data."

Earlier, in 1985, NCRP commented on
Lee82 in a
different manner (Ncrp85,
p.33): "For the production of
thyroid carcinomas, the two radiation types appeared to
be of equal effectiveness at all three doses although the
results did not preclude a relative effectiveness of
iodine-131 of as little as one-third compared to external
radiation."

If one is going to discuss the confidence-limits on a
best estimate, it is certainly not an appropriate practice
to mention only the lower limit. Yet NCRP does not
mention that the Lee82
findings are also consistent with
a higher risk from the slow exposure than from the
acute exposure. There appears to be asymmetry in the
NCRP approach to the Lee82 Study.

UNSCEAR-86 shows the two dose-response curves
from Lee82
practically superimposed on each other (and
both looking supra-linear, not concave-upward), and
comments (Un86,
p.208, para.254): "Thus, there was
no difference in the effectiveness of the two radiations
over the observed range of doses, but a lower
effectiveness of iodine-131 per unit dose (up to a factor
of about 3) could not be excluded on statistical grounds
(Ncrp85)." Thus,
UNSCEAR-86 passes along the
NCRP comment without any criticism of its asymmetry.

To help restore symmetry, we repeat: The best
estimate from Lee82
does not support DREFS and is
also consistent with higher risk at slow-low doses.

Looking at the
Initially Non-Suspect Group :

An obvious question with respect to the Holm Study
is: What would this study have shown if the "initially
suspect" 31 % of the study-population had never been
included?

A Substantial Excess of Thyroid-Cancer :

Because Holm88
does not report what fraction of the
early, discarded cancers occurred in the initially suspect
group, and what fraction occurred in the intially
non-suspect group, the question cannot be answered
with certainty. Indeed, the data do not exist at all for
1951-1957.

We can explore an answer by making an
approximation. Of the total 50 cancers observed after
the 5-year exclusion, 16 cancers occurred in the initially
non-suspect group. The fraction was (16 / 50), or 0.32.
And with the 10-year exclusion, no meaningful change
occurred: The fraction was 8 cancers out of 27 total
cancers, or 0.30. We shall use the approximation that
the fraction which occurred during the 5-year
exclusion was the same as the fraction which occurred
afterwards: 0.32.

Since we estimated (see "Unabridged Results") that
at least 156 thyroid-cancers occurred in the total
study-sample during the first five years of follow-up, we
would approximate that (0.32) x (156 cancers), or 50
cancers came from the initially non-suspect group.
Beyond five years, another 16 thyroid-cancers occurred
in this group, so the estimated total of observed
thyroid-cancers would be 66.

What is the expectation, without radio-iodine, if
the rate in this diseased group is comparable with the
rate in the general population? We are using the same
big "if" used (without discussion) by the Holm Study.

We showed above ("Unabridged Results") that the
expectation in the full cohort during the first five years of
follow-up was 14 cases. Since the initially non-suspect
group represents 69 % of the total study-population, its
expection is (0.69) x (14 cancers) = 9.66 cancers during
the first five years of follow-up. For the follow-up
beyond five years, its expection is (0.69) x (39.4
cancers) = 27.19 cancers during the rest of the
follow-up. Total expectation, if radio-iodine had no
effect, would be (9.66 + 27.19) = 36.85 cancers. And if
the "natural" rate of thyroid-cancer in this special group
is lower than in the general population, the
expectation would also be lower than 36.85 cancers.

So this approach suggests that the relative risk, of
observed cancers over expected cancers, might be (66 /
36.85) = 1.79 if the first five years of follow-up were
included. This is about three-fold higher than the value
of 0.62, reported in the Holm Study with the five-year
exclusion for the initially non-suspect group. And if the
appropriate expected value is even lower than 36.85,
then the risk ratio would be higher than 1.79.

We cannot know. We are only pointing out a good
basis for thinking that the missing data on the first five
years of follow-up might transform a "no provable
excess" report into a highly significant excess. And this
excess might even be wholly due to the radio-iodine
administered. Only a pre-judgment would allow a claim
that it was not.

Presence of a Dose-Response Trend :

One issue which the Holm Study may be capable of
addressing is the issue of dose-response. On this
issue, it does not matter whether the risk ratios are
correct or incorrect (correct meaning that they compare
rates in two groups which are alike in risk, except for
their radiation dose). What matters is how the risk ratios
change (if they do) with rising dose.

Within the results which Holm and co-workers do
report, there is a basis for thinking that there is a strong
dose-response trend in the initially non-suspect group.

Holm and co-workers, in their Table 5, divided the
entire sample of 35,000 patients into three dose-levels
as follows:

In Table 5, the total group (35,000) shows evidence
of a dose-response trend, toward an increasing
incidence of thyroid-cancer with increasing dose of
radio-iodine. Holm and co-workers say (p.1135), "The
thyroid cancer risk increased with increasing
administered I-131 activity (Table 5)." In Table 6, by
contrast, the initially suspect group by itself shows no
evidence of a trend: "There was no relation between
SIR and administered activity of I-131 (Table 6)."

This means that the study's inclusion of the initially
suspect group is tending to dilute and to conceal a
positive dose-response trend in the initially
non-suspect patients. Their dose-response trend
must be even stronger than indicated in Table 5 --
where it is clear despite dilution by the initially suspect
patients. Rising incidence with rising dose is powerful
supportive evidence for causality, of course. It is
regrettable that Holm and co-workers chose not to
evaluate the dose-response trend for the initially
non-suspect patients by themselves, in the same way
that these authors evaluated the initially suspect
patients by themselves.

No Evidence of a Dose-Rate Effect :

We shall continue our exploration of the Holm Study
as if patients who were initially suspected of a thyroid
tumor had never been included, and as if only the 69 %
who had thyroid disorders (but were initially not
suspected of a tumor) were in it.

Now we shall ask if there is any indication of a
dose-rate effect (for instance, reduced risk from slow
exposure compared with acute exposure) in this group,
when we make no pre-judgments -- which means that
we look at the entire follow-up.

Readers who proceed step-by-step, through the two
analyses which follow, will see for themselves that there
is no evidence at all for a dose-rate effect from slow
versus acute exposure.

Even a casual inspection of Studies 1
through 9, in
Chapter 21,
Part 1, demonstrates the delusion of
thinking that reliable risk coefficients (K-values) can be
directly determined for specific sites of cancer.

Let us consider a K-value of 0.02, which is
equivalent to a 2 % increase in spontaneous risk per
rad. If K = 0.02, a dose of 50 rads causes a 100 %
increment above the spontaneous expectation. The
dose which adds as much cancer as the spontaneous
rate is commonly called the doubling dose, so when K =
0.02, the doubling dose is 50 rads. In short, a dose
which doubles the spontaneous rate is one doubling
dose, and a dose which triples the spontaneous rate
represents two doubling doses.

Now, we can inspect the breast-cancer doubling
doses in Chapter 21,
Part 1. The doubling dose in
Study 3 (Massachusetts
Fluoroscopy) was 150 rads, and the doubling dose in
Study 7 (the British Luminizers)
was about 80 rads -- even though the medical X-rays
have a higher Relative Biological Effectiveness than the
gamma rays from radium-226. So there is perhaps a
4-fold difference. (We cannot agree with any analyst
who casually says that breast-cancer risk looks similar
from one site-specific analysis to the next.)

A large range for the doubling dose occurs also in
the in-utero studies of Chapter 21,
Part 1. Even if we narrow the
range by saying that in Study
5 (the Stewart Studies), a half rad causes a 50 % increment
instead of a 94 % increment in childhood cancer, this choice
would make the doubling dose 1 rad. By contrast, in
Study 6 (the MacMahon Study),
0.9 rad provoked a 40 % increment, so (0.9 rad x 2.5) or 2.25
rads would provoke a 100 % increment -- a doubling. Thus
there is more than a 2-fold difference in the magnitude of
doubling dose derived from these studies of a single
cancer-class (childhood cancer).

It is perfectly valid to use such studies to test the
hypothesis of flawless repair. As long as a significant
excess of radiogenic cancer occurs, the excess is
evidence that repair was not flawless. The exact risk
coefficient or doubling dose is irrelevant for such a test.

But it is a very different matter indeed when
analysts attempt to use studies of specific kinds of
cancers (such as childhood cancers, breast-cancers,
thyroid-cancers) to test for an effect of slow versus
acute exposure upon the magnitude of risk, when the
magnitude of the acute effect is so poorly known for
single sites and classes of cancer. Such attempts just
invite large errors, in my opinion.

I do not think site-specific studies are suitable for a
dose-rate analysis, but if such analysis is done
nonetheless, then I think there will be less likelihood of
large errors, if analysts use the very reasonable
approximation that all types of cancer have about the
same fractional increase in their spontaneous rate per
rad, if all other variables are held constant. Until and
unless appropriate evidence develops which shows
otherwise, I would regard myself as skating on
scientifically "thin ice" not to make this
approximation. (Go81,
Chap.10; Go85, pp.19-20.)

All-Cancer K-Value from Our Table 15-L :

If we use the approximation that the thyroid gland is
no more and no less radio-sensitive than other organs,
we must use the all-cancer K-value from our
Table 15-L
in order to calculate the radiogenic expectation
from 50 thyroid-rads in the Holm Study (initially
non-suspect group).

Since 79 % of the Holm-Study patients were women,
with a mean age of 44 years, and since the dose-rate
per day was far below 50 rads, and since the DS86
dosimetry is only supplemental in the A-Bomb Study,
we shall use the low-dose K-value of 0.00615 from the
T65DR dosimetry.

The average energy of beta particles from iodine-131 is about
189 KeV (Strom58). This
may mean a somewhat higher RBE than A-bomb radiation, but we
shall not raise the K-value directly. Instead, we shall
use just the female K-value (which is higher than the
male K-value), and we shall use 50 rads as the thyroid
dose, even though Holm88
states that the initially non-suspect group received a lower
average dose. (Holm88 does not say how much lower.)

So do these calculations from the Holm Study
suggest that the radiation-risk from radio-iodine would
be 3-fold lower than the risk from acute thyroid
exposure?

Not at all. The estimated observed cases in this
sample are 66 cancers, based on reasonable
approximations (see "A Substantial Excess" above).
This is a higher number than 48.25 cases expected
on the basis of acute exposure.

The number 66 is consistent even with a 3-fold
higher K-value from the radio-iodine than from the
A-bomb radiation. With a 3-fold higher K-value, the
radiation-induced cases would grow to (3 x 11.35) or
34.05 cases. So 34.05 radiation-induced cases plus
36.9 spontaneous cases would mean an observation of
70.95 cases -- still in good agreement with an
estimated observation of 66 cases.

Readers who have followed this, step-by-step, can
judge for themselves whether our approximations are
reasonable or not.

We are certainly not claiming that this comparison,
using the all-cancer K-value from the A-Bomb Study,
means that slow dose-rate from iodine-131 is
three-fold more carcinogenic than acute dose-rate.
We have tried to make it clear that we think the Holm
Study is completely inappropriate for addressing the
issue at all.

But, because of the weight given to the Holm Study
by UNSCEAR 1988
and others, we have been obliged to
point out that the Holm Study is consistent with exactly
the opposite conclusions from the ones ascribed to it.

Analysis by the Holm Model :

We are not quite finished, because we promised that
we would search for a dose-rate effect by using the
Holm model too, although we think it is not a good
model for such a purpose.

By "Holm model," we mean the use of a
site-specific K-value, rather than an all-cancer
K-value, to compute the radiogenic expectation of
thyroid-cancer in this study. Holm and co-workers say
(p.1136) that they used the site-specific K-value for
thyroid from the 1985 NIH Report. The NIH Report
(Nih85)
in turn used thyroid incidence data from the
A-Bomb Survivors, Hiroshima plus Nagasaki,
1958-1979 (Nih85, p.255). This would have meant no
correction for the very large overestimate of
neutron-dose at Hiroshima.

Perhaps because of the neutron-error for Hiroshima,
the 1988 UNSCEAR Report (Un88,
p.434, para.209) explicitly recommends the thyroid-cancer
incidence data from Nagasaki alone as "the best," for which
Un88 cites Wakabayashi and co-workers
(Waka83). Nagasaki
data never had a neutron problem. On the
other hand, subdivision of the cities reduces the cases
and thus increases uncertainty in the estimates. In any
case, we should find out if, and how much, the
site-specific K-value differs in Nih85 versus Waka83.

Checking the Site-Specific K-Value :

K-Value Based on Wakabayashi :

The Wakabayashi et al analysis divides the Nagasaki
A-bomb survivors into two classes: Unexposed survivors
and survivors receiving 100 kerma rads and more. On
this basis, these analysts report on the relative risk
(100+ rads versus zero rads) as follows in their Appendix
Table 2:

The ratio of excess relative risk (2.23 / 0.70 = 3.186)
is for the same kerma dose, but not for the same
absorbed dose in the organs from which the cancers
arose. Site-specific analysis requires site-specific
body transmission-factors (Chapter 8,
Part 2). The
body transmission-factor for thyroid is estimated at 0.7
in TR-12-87 (Shi87,
p.43), which is higher than the factor for colon
(see our Table 9-A).

We can proceed by establishing the kerma dose to
which the excess relative risks apply. Using our
Table 9-B,
we calculated the weighted mean dose received by
the Waka83
exposed class (Dose-Groups 5,6,7,8) as
243.7997 kerma rads.

But for equal kerma rads, thyroid is 3.186 times
more sensitive than all organs combined (if you take
site-specific analysis seriously). So the K-value for
thyroid is (3.186 x 0.002871), or 0.009147 per kerma
rad.

But the thyroid's absorbed dose was lower than its
kerma dose, so the K-value will be higher than
0.009147. It needs adjustment for the site-specific
transmission-factor of 0.7 . So we divide (0.009147 /
0.7), and we obtain a site-specific K-value for the
thyroid of 0.013067 per absorbed rad. This is the same
as an excess relative risk of 0.013067 per thyroid-rad.

The value of 0.013067 arises from a population with
an average age at the time of bombing of about 27. The
value might be adjusted downward to apply to the
older study-population in
Holm88, but we will simply
compare it, as it is, to the site-specific K-value from
Nih85.

K-Value from Nih85 :

In the 1985 NIH Report,
Table X-12 (p.261) provides
the following values for "Relative Excess by Exposure
Age and Sex" per thyroid-rad:

Female, Exposure Age 44 = 0.0176 .
Male, Exposure Age 46 = 0.00935 .

The Holm Study (Table 1) has a female to male ratio
of 3.8. If we say m = the male fraction, then 3.8m is the
female fraction, and 4.8m = 1. Therefore m = 0.2083.
And (1-m) or 0.7917 is the female fraction. So the
weighted K-value for the overall Holm Study would be
(0.0176 x 0.7917) + (0.00935 x 0.2083) = 0.01588 .

Results by the Holm Model :

We shall use both site-specific K-values to
compute the radiogenic expectation in the initially
non-suspect group. The radiogenic expectation is (the
spontaneous expectation of 36.9 cancers) x
(site-specific K-value per rad) x (50 rads -- which is an
exaggeration for this group).

With the K-value of 0.013067, based on
Waka83, the
radiogenic expectation = (36.9) x (0.013067) x (50) =
24.1 radiation-induced cancers. The spontaneous
expectation (36.9 cancers) plus the radiogenic cancers
(24.1) = 61.01 cases. And the estimated observed
number was 66 cancers. So there is no indication of
any risk-reduction from the slow delivery from iodine
compared with acute delivery from A-bomb radiation
here.

With the K-value of 0.01588, based on
Nih85, the
radiogenic expectation = (36.9) x (0.01588) x (50) = 29.3
radiation-induced cancers. The spontaneous
expectation (36.9 cancers) plus the radiogenic cancers
(29.3) = 66.2 cases. And the estimated observed
number was 66 cancers. So there is no indication of
any risk-reduction from the slow delivery from iodine
compared with acute delivery from A-bomb radiation
here.

For those who would say, "We want to look only at
the period beyond 5 years," we say the following:

One must avoid distorting the outcome by
pre-judgments which are totally unwarranted. Just
what does anyone know about when
radiation-induced cancers will occur following
radio-iodine in a group of manifestly abnormal people
with diseased thyroids? If you see a large excess of
thyroid cancers in the initially non-suspect group
during the early follow-up, it needs explaining. There
would be no basis whatsoever for simply claiming
that an early excess (if any occurred here) could not
have been caused by the radiation.

Summary on Unwarranted
Conclusions from the Holm Study :

We wish to emphasize a point. Our exploration of
what the Holm Study might have shown, if the 31 % of
initially suspect patients had never been included, is
not a statement by us that we think the initially
non-suspect group is an appropriate group to compare
with the general population. Far from it, as we already
indicated above (see "A Fatally Flawed Study"). The
general population appears to be an unsuitable
control-group for both the initially suspect and initially
non-suspect study-samples.

We have shown our reasons for saying that (A) the
Holm Study in its present state is consistent with
opposite conclusions about dose-rate, and (B) no
one should regard the Holm Study in its present state
as meaningful about anything concerned with DREFS.

In other words, we disagree with its acceptance by
the 1988 UNSCEAR Committee as a piece of notable
human evidence in support of a dose-rate effect and
risk-reduction factors.

Perhaps the Holm Study illustrates the fact that
the peer-review system can perform unevenly. For
instance, reviewers can be ultra-careful about the
choice of control-groups for the in-utero studies (see
Chapter 21,
Part 1), and yet overlook glaring
problems with the control group in a study like the
Holm Study.

6. The Bottom Line

1. For over a
decade, the radiation community has
been using risk reduction-factors to make its estimates
of cancer-risk at acute-low doses and at slow-low
doses. These reduction-factors are based on the
premise that dose versus cancer-response is
concave-upward -- in other words, on the premise that
the risk per rad (cGy) is smaller when dose is either
acute-low or slow-low than when dose is high. This
premise was explicitly stated in 1977 by both
UNSCEAR and ICRP
(see Part 3, above), and has been
echoed again and again by other radiation committees. Of
course, if dose-response is either linear or supra-linear,
it would be a mistake to use risk reduction-factors,
because they would produce underestimates of risk at
both acute-low doses and at slow-low doses. The
inappropriate use of reduction-factors with respect to
Chernobyl-induced cancers is illustrated in
Chapter 24,
Part 7.

2. Since 1977
(TR-1-77, or
Bee77), human
epidemiological evidence has repeatedly shown that the
premise of risk reduction-factors (the premise of a
concave-upward dose-response in humans for
radiation carcinogenesis) is fundamentally flawed. And
the record shows that the radiation committees knew it
by 1980 (see Part 2, above).

3. Nonetheless,
from 1977 through mid-1989, almost all of the radiation
community has subordinated the human evidence against
using risk reduction-factors, in favor of using such factors
on the basis of non-human evidence and cell studies --
"radiobiology." I do not disparage radiobiological
evidence, and we should learn all that we can from
such work. But in science, when predictions from
radiobiology are invalidated by the reality-check of
direct human evidence, the direct evidence must
prevail. This chapter shows that, for years, it has not.

Perhaps it will. In 1988, Warren Sinclair, president of
the NCRP, conceded that in the A-Bomb Study
1950-1982, "... it appears that the dose-effect
response is fitted about as well by a linear as by a
linear-quadratic equation, and this may also influence
risk estimates ..." (Sin88,
p.154). And in 1988, Albrecht Kellerer
(see Chapter 37) offered his opinion
-- after studying the A-bomb survivors through 1985 -- that
"Today, the use of a reduction factor in extrapolation
from high doses to low doses which are relevant for
radiation protection purposes, is less easily defensible
... Although even the extreme hypothesis remains
unfalsifiable, that at the lowest doses there is no excess
cancer incidence, a prudent extrapolation can
nevertheless make use of a linear extrapolation and can
drop the assumption of a reduction factor"
(Kelle88,
p.51; translated from the German by Dr. Rudi
Nussbaum).

Such statements are hedged. Moreover, they are
competing with vigorous pressure in the opposite
direction from some other members of the radiation
community, who are pressing for the ultimate
reduction-factor -- namely, for treating low doses as
safe, and excluding them completely from risk-estimates
(see Chapters 24 and
25).

4. The use of risk
reduction-factors has meant that,
for years, most radiation reports have been presenting
linear estimates as the "upper limit" on risk, despite
human evidence showing that linear estimates represent
either the best values or a lower-limit of risk.

5. There is no
longer any need to extrapolate from
acute high-doses above 100 rads (100 cSv), in order to
make risk-estimates at acute-low or at slow-low doses.
The A-Bomb Study has already provided direct
evidence at low doses for all cancers combined (see
Chapter 13), and it will continue
to do so, provided its
legitimacy as a credible, prospective study is maintained
(as proposed in Chapter 6).